Models for the ultimate development of effective vaccines and immunotherapies that would limit HIV replication can be drawn from naturally occurring examples of immune system-mediated control. Identifying the components, targets, and magnitude of an effective immune response to HIV are important steps toward developing effective vaccines and immunotherapies. Although patients with normal CD4+ T cell counts and low levels of plasma virus are a heterogeneous group, a small subgroup of patients with truly non-progressive HIV infection and restriction of virus replication likely holds important clues to the basis of an effective immune response to HIV. A small subpopulation of HIV-infected individuals (fewer than 0.8%) shows no signs of disease progression over a 10-year period. We have assembled a stringently defined cohort of such patients, termed long-term nonprogressors (LTNPs), or elite controllers. Many of these patients have been infected for 20 years, yet even without receiving antiretroviral therapy, they have experienced no CD4+ T-cell decline and have maintained plasma viral RNA levels below 50 copies per milliliter. We are using cells from these patients to systematically dissect the mechanisms of immune-mediated restriction of virus replication. The HIV-specific T-cell responses of these patients have been studied in extreme detail. Through this project, considerable progress has been made in understanding how the immune system controls HIV. Our prior work indicated that there is a dramatic association between immunologic control and the HLA B*5701 allele, and that the immune response is highly focused on peptides restricted by this allele. This result established both host genetic and functional links between immunologic control and the CD8+ T-cell responses of these patients. More recently, we have found that this focus is specific to HIV and is not found in the response to other pathogens such as hepatitis C virus or cytomegalovirus. LTNPs and progressors do not differ in the frequency of HIV-specific T cells or in the ability to recognize the autologous virus. The finding of high frequencies of CD8+ T cells specific for the patients virus in both LTNPs and progressors strongly suggested that differences between responses of these patient groups were qualitative rather than quantitative in nature. One important qualitative difference in the HIV-specific immune response that distinguishes LTNPs from progressors is the maintenance of HIV-specific CD8+ T cells with a high proliferative capacity. This proliferation parallels perforin expression required for effective killing of HIV-infected CD4+ T cells. We have previously established the properties of the HIV-specific CD8+ T-cell response that are tightly associated with the LTNP phenotype. Although the HIV-specific CD8+ T cells of LTNPs have a greater capacity to proliferate and increase their number of molecules responsible for killing HIV-infected cells, the mechanism(s) by which these properties translate into effective immunologic control of HIV has remained unknown. Most current assays are not sufficiently powerful to establish if differences in HIV-specific CD8+ T-cell function are determined by frequency, CD8+ T-cell proliferation, preferential target or effector cell death, or the mechanism of HIV-infected cell elimination. To better understand the mechanisms of immunologic control, we devised a method to measure HIV-infected cell elimination on a per-cell basis. Measured on a per-cell basis, HIV-specific CD8+ T cells of LTNPs efficiently eliminated primary autologous HIV-infected CD4+ T cells. This effective killing was clearly distinguishable from the responses of progressors over a very broad range of effectors to HIV-infected targets. Progressor cells did not mediate effective killing even at high effector-to-target ratios. Defective cytotoxicity of progressor effectors could be restored in vitro. These results establish an effector function and a mechanism that clearly segregate with immunologic control of HIV. One of the original goals of our work in LTNP was to provide insights regarding important elements of the cellular immune response that should be induced in vaccination. Although cytotoxic capacity clearly distinguishes those with immunologic control in the setting of chronic infection, it may not necessarily be the operative mechanism in control induced by an HIV vaccine. Previously, direct measurements of recall cytotoxic capacity assessed by granzyme B target cell activity and infected CD4+ T-cell elimination had not been applied to recipients of HIV vaccines. We recently examined the HIV-specific CD8+ T-cell cytotoxic capacity of HIV-1-uninfected recipients of the Merck Ad5/HIV trivalent vaccine. A very high profile efficacy trial employing this vaccine was the Step study, a phase IIB test-of-concept trial involving 3,000 HIV-negative individuals at high risk of HIV infection. We observed that the ability of vaccine-induced HIV-specific CD8+ T cells to kill primary autologous HIV-infected targets was relatively low and not comparable to responses we have previously associated with immunologic control. We observed that the cytotoxic responses of vaccine recipients carrying HLA class I alleles associated with nonprogressive HIV infection, e.g., B*27, B*57 and B*58, were significantly greater than those of individuals not possessing these alleles. These findings suggest that the relatively poor ability of this vaccine to reduce viral loads upon natural infection is potentially attributable to the relatively poor induction of cytotoxic capacity. To better understand the qualitative features of effective HIV-specific immunity, in 2012 we examined the T cell receptor (TCR) clonal composition of CD8+ T-cells recognizing conserved HIV p24-derived epitopes in HLA-B*5701+ long-term nonprogressors / elite controllers and HLA-matched progressors. Both groups displayed oligoclonal HLA-B5701-restricted p24-specific CD8+ T cell responses with similar levels of diversity and few public clonotypes. Thus, HIV-specific CD8+ T cell responses in LTNP/EC are not differentiated from those of progressors on the basis of clonal diversity or TCR sharing. In 2012 we described four unique individuals who were distinct from conventional LTNP/EC in that they had extraordinarily low HIV burdens and comparatively weak immune responses. The four unique cases were distinguished from typical LTNP/EC based on weakly reactive Western blots, undetectable plasma viremia by a single copy assay, extremely low to undetectable HIV DNA levels and difficult to isolate replication-competent virus. All four had at least one protective HLA allele and CD8+ T-cell responses that were disproportionately high for the low antigen levels, but comparatively lower than those of typical LTNP/EC. These unique individuals exhibited extraordinary suppression over HIV replication and, therefore, higher-level control than has been demonstrated in previous studies of LTNP/EC. Additional insight into the full spectrum of immune-mediated suppression over HIV replication may enhance our understanding of the associated mechanisms, which should inform the design of efficacious HIV vaccines and immunotherapies. Taken together our work suggests that cytotoxic capacity is a clear correlate of immunologic control of HIV in chronic infection and may also be an important immune correlate in vaccinees. In addition, the greater cytotoxic capacity induced in vaccine trials among participants with protective alleles is consistent with associations between MHC alleles and viral load in vaccinees. Over the coming years we are optimistic that this work will provide a long-sought after T cell correlate of immunity that will accelerate vaccine development.